The goal of this project is to establish the functional relevance of exogenous cannabinoids in modulating responsiveness of microglia to the human immunodeficiency virus-1 (HIV-1) trans-activating (Tat) protein. Microglia are resident macrophages of the central nervous system (CNS) that serve as principal targets for HIV-1. These cells are productive hosts for HIV-1 and elicit a plethora of cytokines, monokines, and neurotoxic factors in response to infection. Included among these are the virus envelope glycoprotein gp120 and the virus-specified gene product Tat. While both proteins can activate uninfected microglia and immunocytes in the CNS resulting in an expansive release of inflammatory and neurotoxic factors, the production of Tat by HIV- infected cells is not affected by currently available anti-retroviral drugs since these target the reverse transcriptase and protease enzymes of HIV. This observation, taken together with the fact that Tat is released extracellularly, articulates a rationale for assessment of its role in HIV neuropathogenesis in the current highly- active antiretroviral therapy era. Tat exerts robust chemotactic properties and may recruit uninfected microglia and other immunocytes to focal areas of HIV-1 infection. The combined action of chemotaxis-driven aggregation of immunocytes at focal areas of infection and elicitation of inflammatory factors may be a major contributive factor in the development of HIV-associated neurocognitive disorder (HAND). Cannabinoids have been shown to modulate the functional activities of immune cells, including those of microglia. The preponderance of these effects has been inhibitory and mediated through the CB2 cannabinoid receptor (CB2R). Since this receptor is expressed by microglia during various states of neuroinflammation, it has the potential to serve as a cell-selective molecular target for ablating untoward immune responses, including those engendered by Tat. Thus, the CB2R may serve as a template for the generation of specific ligands devoid of psychotropic properties and rationally designed based on the critical features of the receptors with which they interact. In the proposed study we will test the hypothesis that select exogenous cannabinoids act through the CB2R, and possibly other cannabinoid receptors, to dampen microglial inflammatory responses to Tat. The following specific aims will serve as guidelines to the research: (1) to define the in vitro effects of exogenous cannabinoids on human microglial responsiveness to the HIV protein Tat, (2) to establish the mode of action through which exogenous cannabinoid alters microglial responsiveness to the HIV protein Tat, and (3) to establish the relevance of the effects of exogenous cannabinoid on microglial responsiveness to Tat in the context of human mixed glial cultures and mouse brain slice cultures.